July 25, 2006 Researchers at the Virginia Bioinformatics Institute at Virginia Tech have developed a computational model that allows scientists to better understand the metabolism and toxicity of the HIV/AIDS drug zidovudine (azidothymidine, AZT).
AZT is used successfully as part of Highly Active Anti-Retroviral Therapy (HAART) to control the level of the human immunodeficiency virus in HIV-infected individuals. However, long-term use of AZT may lead to side-effects in some patients. David Samuels and coworkers are interested in finding out whether the toxic side effects of AZT can eventually be minimized or even eliminated. For this purpose, they have been developing a detailed computational model that allows scientists to simulate the biochemical reactions that take place when AZT is metabolized in cells, including their mitochondria, under different metabolic conditions. Drugs like AZT may interfere with DNA replication in the mitochondria, the energy factories of our cells, and can lead to potentially fatal side effects in patients undergoing HAART treatment.
“HAART is one of the biggest success stories in modern medicine. The goal of our work is to help improve this successful treatment by understanding the toxic effects that AZT can have in some people. There are many different ways that AZT could possibly interfere with mitochondria to cause the toxic side-effects. Our job is to model these proposed toxicity mechanisms to see which ones could actually lead to the mitochondrial defects found in AIDS patients, ”said Dr Samuels, assistant professor at Virginia Bioinformatics Institute. “It is possible that no single mechanism is responsible for the toxicity, but that instead a combination of multiple effects is needed. That is the kind of problem that needs a systems biology approach.”
When AZT reaches a cell, it is subject to some of the same metabolic modifications or phosphorylation events that are encountered by the four naturally occurring deoxynucleosides, the building blocks used to make DNA. However, modified AZT molecules lack a specific chemical group (a hydroxyl group) that would allow DNA replication to continue. This results in premature termination of DNA synthesis. It is thought that the triphosphorylated form of AZT can enter the mitochondrial matrix, the inner core of the mitochondrion, and disrupt the replication of mitochondrial DNA by prematurely terminating DNA synthesis.
“We’re just starting our work. It is too early to say what the mechanism of mitochondrial toxicity of AZT is. The inhibition of deoxynucleoside metabolism is one possibility. The incorporation of AZT into mitochondrial DNA is another,” added Samuels. “The detailed computational model that we have developed should allow researchers to explore different hypotheses as to why AZT can lead to such debilitating side effects in some patients undergoing anti-retroviral treatment.”
This research is supported by National Institutes of Health grant DK070533.
The Virginia Bioinformatics Institute (VBI) at Virginia Tech has a research platform centered on understanding the “disease triangle” of host–pathogen–environment interactions in plants, humans and other animals. By successfully channeling innovation into transdisciplinary approaches that combine information technology and biology, researchers at VBI are addressing some of today’s key challenges in the biomedical, environmental and plant sciences.
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